OMICS A Journal of Integrative Biology

Volume 24, Number 0, 2020

Review Article
ª Mary Ann Liebert, Inc.
DOI: 10.1089/omi.2020.0122

Coronavirus Disease-2019 Treatment Strategies

Targeting Interleukin-6 Signaling and Herbal Medicine

Kevin Dzobo,1,2 Harry Chiririwa,3 Collet Dandara,4 and Witness Dzobo5,6

Abstract

Coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2
(SARS-CoV-2) is evolving across the world and new treatments are urgently needed as with vaccines to prevent
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the illness and stem the contagion. The virus affects not only the lungs but also other tissues, thus lending support
to the idea that COVID-19 is a systemic disease. The current vaccine and treatment development strategies ought
to consider such systems medicine perspectives rather than a narrower focus on the lung infection only. COVID-
19 is associated with elevated levels of the inflammatory cytokines such as interleukin-6 (IL-6), IL-10, and
interferon-gamma (IFN-c). Elevated levels of cytokines and the cytokine storm have been linked to fatal disease.
This suggests new therapeutic strategies through blocking the cytokine storm. IL-6 is one of the major cytokines
associated with the cytokine storm. IL-6 is also known to display pleiotropic/diverse pathophysiological effects.
We suggest the blockage of IL-6 signaling and its downstream mediators such as Janus kinases ( JAKs), and
signal transducer and activators of transcription (STATs) offer potential hope for the treatment of severe cases of
COVID-19. Thus, repurposing of already approved IL-6-JAK-STAT signaling inhibitors as well as other anti-
inflammatory drugs, including dexamethasone, is under development for severe COVID-19 cases. We conclude
this expert review by highlighting the potential role of precision herbal medicines, for example, the Cannabis
sativa, provided that omics technologies can be utilized to build a robust scientific evidence base on their clinical
safety and efficacy. Precision herbal medicine buttressed by omics systems science would also help identify new
molecular targets for drug discovery against COVID-19.

Keywords: COVID-19, SARS-CoV-2, cytokines, interleukin-6, JAK, STAT, drug repurposing, natural products

Introduction Studies have shown that COVID-19 is accompanied by

enhanced release of cytokines, including interleukin-6 (IL-6),

C OVID-19 pandemic caused by the severe acute respi-

ratory syndrome coronavirus-2 (SARS-CoV-2) is
evolving across the world with seismic and unprecedented
adverse impacts on planetary health (Huang et al., 2020). The
virus affects not only the lungs but also other tissues, thus
lending support to the idea that coronavirus disease-2019
(COVID-19) is a systemic disease. While many infected
patients do not show active or severe symptoms, the elderly
and those with concurrent chronic illnesses such as diabetes,
hypertension, and obesity are at an elevated risk for severe
COVID-19 and attendant mortality.
IL-8, IL-10, and tumor necrosis factor-alpha (TNF-a) (Hir-
ano and Murakami, 2020; Moore and June, 2020; Zhang
et al., 2020b). Although cytokines are important in the
elimination of an infection, enhanced release of cytokines
might also cause serious adverse effects, including organ
damage and failure and death (Carcillo, 2003; Chaudhry
et al., 2013; Netea et al., 2003). For example, decreased
cluster of differentiation (CD) 4 and CD8 cells has been
observed in most COVID-19 cases (Xu et al., 2020). The
COVID-19 pandemic calls for disruptive innovations in drug
discovery and the broadening of our screening for drug

1
International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town, South Africa.
2
Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical
Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
3
Department of Chemical Engineering, Vaal University of Technology, Vanderbijlpark, South Africa.
4
Division of Human Genetics, Department of Pathology, Institute for Infectious Disease and Molecular Medicine, Faculty of Health
Sciences, University of Cape Town, Cape Town, South Africa.
5
Immunology Department, Pathology, University Hospital Southampton, Southampton, United Kingdom.
6
Faculty of Science, University of Portsmouth, Portsmouth, United Kingdom.

1
 2 DZOBO ET AL.
candidates to include natural products and/or the repurposing
of already existing drugs (Cao et al., 2020; Dong et al., 2020;
Lim et al., 2020; Zhu et al., 2020).
One strategy for treatment of COVID-19, and specifically,
therapeutic targeting of the ‘‘cytokine storm,’’ may call for
combinatorial drugs. However, we also argue that robust
COVID-19 treatments must be informed by both the viral
entry mechanism into the human body and secondary effects
such as cytokine release syndrome.
The severe cases of COVID-19 are associated with ele-
vated levels of inflammatory cytokines such as interleukin-6
(IL-6), IL-10, and interferon-gamma (IFN-c) in the circula-
tion (Liu et al., 2020a; Mehta et al., 2020; Michot et al.,
2020). An elevated level of cytokines or cytokine storm has
been linked to fatal disease, suggesting the prevention or the
repression of this cytokine storm is important in effective
therapeutic treatment of COVID-19.
One of the notable cytokines associated with COVID-19 is
IL-6. Several in vitro and animal studies have shown that IL-6
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has dose- and time-dependent effects, and it is not surprising
that increased release of this cytokine has deleterious effects
on the human body (Hunter and Jones, 2015; Steyn et al.,
2019; Taniguchi and Karin, 2014). Potential drugs to target
and eventually suppress the ‘‘cytokine storm’’ have come
from the repurposing of old drugs, novel and innovative
therapeutics, and natural products. Currently, several com-
pounds and drugs are undergoing evaluation in treating
COVID-19 in several clinical trials.
The coronavirus and SARS-CoV-2 specifically make use of
the angiotensin-converting enzyme-related carboxypeptidase
(ACE2) receptor to enter cells. Several cells have been shown
to express the ACE2 receptor, including tissues important in
transporting oxygen throughout the body as well as immune
cells, macrophages, and monocytes, for example ( Jia et al.,
2005; Sims et al., 2005). A recent observational study showed
that the expression of the ACE2 receptor and low immune cell
count is associated with disease severity (Yang et al., 2020a).
The ‘‘Cytokine Storm’’ and IL-6 Signaling
‘‘A’’ or ‘‘the’’ cytokine release syndrome, occurs when the
human body responds to the presence of an infection or drugs,
is marked by increased levels of inflammatory cytokines, and
has been associated with death in patients infected with
SARS-CoV-2 (Mehta et al., 2020; Moore and June, 2020;
Zhang et al., 2020a). It is known that viral infections activate
the innate immune response. Uncontrolled activation of the
immune system results in elevated levels of inflammation and
can be fatal (Moens and Meyts, 2020).
COVID-19 is associated with a cytokine storm that causes
several immune cells to be recruited to the infection site to
remove pathogens (Fung and Liu, 2014). It is known that
other coronaviruses such as SAR-CoV and Middle East re-
spiratory syndrome coronavirus (MERS-CoV) can cause in-
flammatory responses and cytokine dysregulation just like
SARS-CoV-2, but these are associated with IL-17 ( Josset
et al., 2013; Naqvi et al., 2020).
In the case of SARS-CoV-2, proinflammatory cytokines in
the lungs lead to increased levels of immune cells in the lungs
(Channappanavar et al., 2016; Runfeng et al., 2020). Patients
with COVID-19 display reduced levels of suppressor of cy-
tokine signaling (SOCS) 3, which is needed in control of IL-6
signaling (Okabayashi et al., 2006). Overall, although there
are some small differences in the SARS-CoV, SARS-CoV-2,
and MERS-CoV infections, there are great differences in the
number of fatalities associated with each virus, with SARS-
CoV-2 causing more deaths than the other two viruses. Cy-
tokine release syndrome is also observed when sepsis occurs
(Borrega et al., 2019; Shimabukuro-Vornhagen et al., 2018;
Singleton et al., 2005).
Several reports have reported high levels of IL-6 in COVID-
19 patients (Chen et al., 2020b; Luo et al., 2020; McGonagle
et al., 2020). These high levels of cytokines have been asso-
ciated with respiratory distress, including death (Chen et al.,
2020a; Ruan et al., 2020). IL-6 is also known to influence the
expression of proteins, including the C-reactive protein (CRP),
itself a biomarker of sepsis (Nargis et al., 2014; Vincent et al.,
2011). Indeed, both IL-6 and CRP are used as biomarkers in
critical ill patients (Adamzik et al., 2010; Miguel-Bayarri et al.,
2012). The cytokine storm observed in COVID19 patients has
been associated with the development of acute respiratory
distress syndrome (ARDS) (Ye et al., 2020). Cytokines levels,
including IL-6, are significantly elevated in COVID-19 pa-
tients with ARDS (Fan et al. 2020b; Ye et al., 2020). In ad-
dition, the cytokine storm severity is linked to organ failure and
mortality rate (Bhaskar et al., 2020).
Infection of several immune cells by the coronavirus
causes the release of inflammatory cytokines as well as IL-6.
Several cells, including fibroblasts, dendritic cells, lympho-
cytes, and endothelial cells, are known to produce large
quantities of IL-6 (Dzobo, 2020a, 2020b; Dzobo and Dan-
dara, 2020; Jones and Jenkins, 2018; Steyn et al., 2019).
These immune cells also include macrophages and mono-
cytes. IL-6 was first characterized as interferon-B2, but is
now known to be a superfamily consisting of many growth
factors, cytokines, and chemokines (Garbers and Scheller,
2013; Rose-John, 2003, 2018; Rose-John et al., 2007). In-
itially best known for its participation in immune responses,
recent data show that the IL-6 superfamily has trophic,
metabolic, as well as endocrine functions in several tissues
and organs (Hunter and Jones, 2015; Rath et al., 2015). IL-6
has been shown to induce the transcription of CRP (Slaats
et al., 2016; Yoshizaki, 2011).
Members of the IL-6 superfamily signal through gp130
(CD130), a transmembrane protein expressed on membranes
of cells (Munoz-Canoves et al., 2013; Rose-John, 2018). IL-6
signaling occurs through two main pathways known as the
classic and trans-signaling mechanisms (Fig. 1) (Hirano, 1998;
Rose-John, 2018; Rose-John et al., 2007). The IL-6 receptor
can be membrane bound or soluble with both forms binding to
IL-6 with similar affinity (Gearing et al., 1992). A third and not
well described IL-6 signaling pathway is referred to as the
trans-presentation signaling (Heink et al., 2017).
The classical signaling activation occurs when IL-6 binds
to the membrane-bound receptor (interleukin-6 receptor [IL-
6R]), also referred to as CD126 (Tanaka et al., 2014a). The
receptor then forms a complex with a homodimer of gp130
protein, resulting in the transmission of the intracellular
signal (Munoz-Canoves et al., 2013; Rose-John, 2018; Rose-
John et al., 2007).
Cells such as neutrophils, macrophages, natural killer
cells, and hepatocytes are the major cell types expressing the
IL-6 receptor (Nishimoto and Kishimoto, 2006; Scheller
and Rose-John, 2006). The activation of the IL-6 classical
 EMERGING COVID-19 TREATMENT STRATEGIES
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FIG. 1. Interleukin-6 signaling cascade and potential inhibitors of the pathways. Figure is adapted from Dzobo and
Dandara (2020).
signaling can cause pleiotropic effects on the above-
mentioned cells through the action of the Janus kinases
( JAK) and the signal transducer and activator of transcription
(STAT) (Murray, 2007). Pleiotropic effects of IL-6 signaling
on immune cells have been shown to contribute to the de-
velopment of the ‘‘cytokine storm’’ (Kang et al., 2019; Zhang
et al., 2020a). This complexity and specificity have important
implications for targeted manipulations.
Several studies showed that splicing and proteolytic pro-
cessing result in the formation of the soluble form of the
receptor, which is found in body fluids (Munoz-Canoves
et al., 2013; Rose-John et al., 2007). Trans-signaling occurs
when circulating IL-6 binds to its soluble IL-6 receptor (sIL-
6R) and activates the JAK-STAT signaling cascade (Peters
et al., 1998). The IL-6-sIL-6R complex formed can also bind
to gp130 homodimer on cells with no membrane-bound IL-6
receptor such as endothelial cells, in a way expanding
influence and effect of IL-6 (Munoz-Canoves et al., 2013;
Rose-John et al., 2007).
Activation of both IL-6 classical and trans-signaling cau-
ses the secretion of several growth factors and cytokines that
contribute to the presence of leaky blood vessels that are
associated with respiratory distress ( Joly et al., 2020; Ma-
tacic, 2020; Wadman et al., 2020). In this review, we discuss
potential strategies to target IL-6 signaling in the treatment of
COVID-19 patients (Fig. 1). We also present alternative
treatment strategies being undertaken.
Cytokine release has also been reported in patients on
immunotherapy. For example, patients receiving chimeric
antigen receptor (CAR) T therapy can also show increased
cytokine release (Maude et al., 2014; Porter et al., 2018;
Teachey et al., 2016). T cells expressing the CAR molecules
will bind to cancer cells, resulting in an immune reaction that
3
clears the body of the cancer cells (Fitzgerald et al., 2017; Xu
and Tang, 2014). Thus, while the chimeric antigen receptor T
cell immunotherapy (CAR T) is very promising in cancer
treatment, it can also cause life-threatening effects such as
enhanced cytokine release that is associated with organ failure
(Norelli et al., 2018; Wang and Han, 2018). Norelli et al.
(2018) demonstrated that IL-1 and IL-6 released by monocytes
are needed for the development of cytokine release syndrome
and neurotoxicity in patients undergoing CAR T.
To resolve the elevated cytokine release in patients receiv-
ing CAR T, inhibitors of IL-6 signaling have been used. For
example, tocilizumab was used to treat cytokine release syn-
drome in a patient receiving CAR T (Grupp et al., 2013). As a
result, tocilizumab has been suggested as treatment for cyto-
kine release syndrome associated with COVID-19 (Liu et al.,
2020a; Zhang et al., 2020a). Several case reports of patients
being treated with tocilizumab and successfully recovering
have been published (Luo et al., 2020; Michot et al., 2020). In
these reports, patients with severe COVID-19 mostly recov-
ered from fever and did not require the use of ventilators a few
days after treatment with IL-6 signaling inhibitors.
Currently, several clinical trials on IL-6 signaling inhibi-
tion in treating serious cases of COVID-19 are being under-
taken (Ingraham et al., 2020; Liu et al., 2020a; McGonagle
et al., 2020; Moore and June, 2020). Inhibition of the IL-6
signaling cascade can be at different levels starting by the
binding of IL-6, inhibiting IL-6 from binding to its receptor,
and inhibition of downstream mediators such as JAKs and
STATs (Ingraham et al., 2020; Nishimoto and Kishimoto,
2006; Steyn et al., 2019; Zhang et al., 2020a, 2020b).
In this analysis, we emphasize that different concentrations
of these inhibitors are likely to have contrasting effects in
COVID-19 as observed with IL-6 in muscle tissues (Steyn
 4 DZOBO ET AL.
et al., 2019). In addition, inhibition of IL-6 signaling down-
stream mediators such as JAKs and STATs is likely to be
more effective as it affects both classical and trans-signaling
(Peters et al., 1998; Rose-John et al., 2007; Steyn et al., 2019).
Inhibitors of IL-6 signaling that binds to IL-6 can inhibit both
classical and trans-signaling.
Drug Repurposing/Reuse for COVID-19
Tocilizumab is currently prescribed for conditions such as
rheumatoid arthritis and can be repurposed for COVID-19
due to its effect against enhanced cytokine release. It is im-
portant to note that anti-IL-6 inhibitors are also currently being
used in the treatment of many cancers. The IL-6-JAK-STAT3
pathway, for example, is abnormally activated in several
cancers and has been linked with a poor prognosis (Chen et al.,
2013a, 2013b, 2013c; Sanguinete et al., 2017). Furthermore,
activation of IL-6-JAK-STAT cascade is associated with im-
mune repression (Tanaka et al., 2014a, 2014b).
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Several inhibitors of the IL-6-JAK-STAT signaling have
been authorized by the Food and Drug Administration (FDA)
and European Medicines Agency (EMA), and can be re-
purposed to ameliorate the inflammation and cytokine release
syndrome observed in severe cases of COVID-19. Inhibitors
that target IL-6 directly include siltuximab, while tocilizu-
mab targets its receptor, IL-6R. Siltuximab can therefore be
used to reduce the amount of IL-6 in circulation as well as
downstream mediators such as STAT3 (Fizazi et al., 2012).
Inhibitors of IL-6 signaling downstream mediators such as
JAKs include pacritinib, ruxolitinib, and tofacitinib.
Single therapeutic agents such as remdesivir and tocili-
zumab have been shown to have mixed results in the treat-
ment of COVID-19 (Alzghari and Acuña, 2020; Grein et al.,
2020; Wang et al., 2020c). Another treatment option is the
use of exosomes derived from bone marrow, with several
studies demonstrating their efficacy against inflammatory
diseases (Morrison et al., 2017; Wang et al., 2018). The
classical IL-6 signaling is observed in cells expressing the IL-
6R, including muscle cells, immune cells, and endothelial
cells. In the absence of IL-6R, trans-signaling can occur as
gp130 is expressed by all cells (Hibi et al., 1990). Thus, an
inhibitor of both classical and trans-signaling such as tocili-
zumab can prevent IL-6-mediated effects.
Tocilizumab can bind both cell-bound and soluble IL-6R,
and thus inhibits the main IL-6 signaling pathways (Dzobo
and Dandara, 2020; Hennigan and Kavanaugh, 2008). Toci-
lizumab has been approved for several conditions, including
rheumatoid arthritis, and has been shown to be effective
against colorectal and pancreatic cancers (Dijkgraaf et al.,
2015; Grivennikov et al., 2009; Navarro et al., 2014). Grupp
et al. (2013) demonstrated that tocilizumab can be used for
the treatment of cytokine release syndrome. Another study by
Winkler et al. (1999) also showed that tocilizumab can be
used for cytokine release syndrome. As the cytokine release
syndrome is resolved, the amount of tocilizumab adminis-
tered can be reduced. Tocilizumab can be given as a mono-
therapy or in combination with methotrexate.
Several clinical trials are underway to study tocilizumab in
COVID-19 patients (Table 1). For example, a phase 2 clinical
study is enrolling patients with severe COVID-19 disease to
be treated with tocilizumab (Clinical Trials Identifier:
NCT04317092). Yet another phase 3 study is enrolling patients
to evaluate the efficacy of tocilizumab in severe COVID-19
disease cases (Clinical Trials Identifier: NCT04320615). In
addition, another phase 3 clinical study to evaluate the clinical
efficacy and safety of tocilizumab relative to placebo in nearly
300 hospitalized adult patients with severe COVID-19 is un-
derway (Clinical Trials Identifier: NCT04412772).
Tocilizumab is also being examined in clinical trials, in
combination with other drugs. For example, a study is re-
cruiting to evaluate the use of tocilizumab in combination with
other drugs (e.g., azithromycin) for the treatment of hospital-
ized adult patients with COVID-19 (Clinical Trials Identifier:
NCT04332094). A phase 4 clinical trial study to evaluate the
therapeutic value of tocilizumab as a single dose in patients
with SARS-CoV2 infection is recruiting (Clinical Trials
Identifier: NCT04377750). Another clinical trial is evaluating
the effect of early and late administration of tocilizumab in
patients with COVID-19 pneumonia, who require mechanical
ventilation (Clinical Trials Identifier: NCT04346355).
Given the pleiotropic effects of IL-6, the inhibition of IL-6
signaling must be done with caution. Only critical patients
displaying elevated levels of IL-6 must be treated with IL-6
inhibitors such as tocilizumab. It would appear that sup-
pression of IL-6 is a much better option than complete inhi-
bition of IL-6 signaling, given that IL-6 has other functions in
organs such as muscles (Steyn et al., 2019). Lessons learnt
from the effect of IL-6 on muscle cells demonstrate that IL-6
has both dose- and time-dependent effects and this needs to
be taken into consideration when using IL-6 inhibitors in
COVID-19 treatment (Steyn et al., 2019). In addition, our
recent study demonstrated that negative regulators such as
SOCS1 and SOCS3 can inhibit the effect of IL-6 signaling
(Steyn et al., 2019). Thus, activation of SOCS1 and SOCS3
expression in severe COVID-19 patients may be a natural
way of suppressing the effect of elevated IL-6.
The absence of any proven and effective therapeutic
treatment for COVID-19, especially the severe cases, has
prompted scientists to repurpose well-known drugs and
compounds, including chloroquine, hydroxychloroquine,
and dexamethasone. While there is evidence pointing to the
effectiveness and safety of chloroquine use in patients with
several other conditions, its use in COVID-19 treatment
requires clinical trials and adherence to registered inter-
vention protocols, and protocols still to be devised. Several
studies have reported the effectiveness of chloroquine at
blocking viral replication (Colson et al., 2020; Wang et al.,
2020a). A less toxic derivative of chloroquine, hydroxy-
chloroquine, was suggested to be more effective than
chloroquine, but clinical studies have not lent evidence to
that end.
The two related drugs chloroquine and hydroxychloroquine
are used mainly for malaria treatment (Tanenbaum and Tuf-
fanelli, 1980). Studies have shown that these two drugs have
antiviral effects against human immunodeficiency virus (HIV),
for example (Devaux et al., 2020; Savarino et al., 2003, 2006).
The drugs work through inhibition of viral entry into host cells.
Another suggested mechanism through which these drugs
work is by inhibition of glycosylation of synthesized proteins
(Devaux et al., 2020; Savarino et al., 2003). Several clinical
trials involving hydroxychloroquine for the treatment of ac-
quired immune deficiency syndrome (AIDS) treatment have
been undertaken with contrasting results (Molina et al., 2020;
Paton et al., 2012; Piconi et al., 2011).
 EMERGING COVID-19 TREATMENT STRATEGIES 5

Table 1. Clinical Trials Currently Underway (August 2020) on Tocilizumab in Patients

with Coronavirus Disease-2019
Clinical trial identifier Study design Country No. of patients and age Drugs
NCT04412772 Interventional, randomized United States 300 and 18–95 years Tocilizumab
and placebo
NCT04403685 Interventional, randomized Brazil 150 and 18 years and older Tocilizumab
NCT04377750 Interventional, randomized Israel 500 and 18 years and older Tocilizumab
NCT04377659 Interventional, randomized United States 40 and 18 years and older Tocilizumab
NCT04372186 Interventional, randomized United States 379 and 18 years and older Tocilizumab
and placebo
NCT04370834 Interventional United States 217 and 2 years and older Tocilizumab
NCT04363853 Interventional Mexico 200 and 18–90 years Tocilizumab
NCT04363736 Interventional, randomized United States 100 and 18 years and older Tocilizumab
NCT04361552 Interventional, randomized United States 180 and 18 years and older Tocilizumab
NCT04346355 Interventional, randomized Italy 398 and 18 years and older Tocilizumab
NCT04335305 Interventional, randomized Spain 24 and 18–80 years Tocilizumab and
pembrolizumab
NCT04335071 Interventional, randomized Switzerland 100 and 30–80 years Tocilizumab
and placebo
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NCT04317092 Interventional Italy 400 and all ages Tocilizumab

Contrasting data have also been obtained in trials of hy-
droxychloroquine in the treatment of COVID-19 treatment
(Gautret et al., 2020a, 2020b; Molina et al., 2020). Recently,
both World Health Organization (WHO) and the FDA have
removed their recommendations of using hydroxychloroquine
in the clinic as a treatment for COVID-19 (Colson et al., 2020;
Li and De Clercq, 2020; Liu et al., 2020c). As a pandemic
presents by its very nature a constantly moving front, real-
time, evidence-based, and continuous evaluation of emerging
potential therapeutic candidates will be necessary.
Corticosteroid therapy has been suggested to alleviate
some of the conditions associated with COVID-19 such as
inflammation. Thus, corticosteroid therapy, including the use
of dexamethasone and hydrocortisone, offers prospects in
alleviating inflammation, and thus might increase the chances
of survival of patients. Dexamethasone is available to pa-
tients and a recent clinical trial showed that it can reduce
deaths by almost a third in ventilated patients and a fifth in
other patients receiving oxygen only (Clinical Trial Identi-
fier: NCT04381936; RECOVERY trial; www.recoverytrial
.net). However, further studies are required as the study re-
ports on a particular patient phenotype.
On a general note, dexamethasone is considered safe for use
(RECOVERY Collaborative Group et al., 2020; Theoharides
and Conti, 2020). However, the use of dexamethasone appears
to be beneficial to those with severe pneumonia rather than
those with less severe pneumonia ( Johnson and Vinetz, 2020).
There is a potential for high blood glucose levels during
dexamethasone treatment (Russell et al., 2020). If dexametha-
sone is used over a long period of time, conditions such as
hypertension and weight gain may be observed (Akhtar et al.,
2020). Another corticosteroid, methylprednisolone, is also un-
der clinical trials, together with antibiotics in treating COVID-
19 (Alberici et al., 2020; Fan et al., 2020a; Liu et al., 2020b).
Natural Products and Herbal Medicines
for COVID-19
The Intergovernmental Science-Policy Platform on Bio-
diversity and Ecosystem Services has recently cautioned that
‘‘around one million animal and plant species are now
threatened with extinction’’ (Dı́az et al., 2019). Planetary
ecosystem biodiversity is an essential foundation for ther-
apeutics innovation (Newman and Cragg, 2016). To this
end, natural products and herbal medicines have been used
as remedies for several conditions, including infectious
diseases, since time immemorial (Dandara et al., 2020;
Thomford et al., 2016, 2018a, 2018b). The use of plants as
part of traditional medicine is practiced in developed
countries as well, although it is more prominent in devel-
oping countries in our view.
The compounds in plants have been studied in relationship
to their effects on the immune system, as well as for their
prospects for antibacterial, antiviral, and antifungal medici-
nal effects. Currently, there are no vaccines or effective drugs
approved to treat or prevent COVID-19. Hence, novel mo-
lecular leads can be usefully derived by considering tradi-
tional medicine and plant resources, as well as part of the
current and future efforts for COVID-19 therapeutics inno-
vation. The coronavirus encodes several proteins, of which
Papain-like protease (Plpro), 3C-like protease (3Clpro), and
the spike (S) protein are those that have been well studied so
far (Goel and Goel, 2020). These proteins are used for cel-
lular entry and viral replication. The S protein of SARS-CoV-
2 is important for the attachment and pathogenesis of the
virus (Hoffmann et al., 2020). Plant resources warrant further
consideration in relationship to targeting these pathways.
In the past, phenolic plant compounds and Isatis indigotica
root extracts were found to inhibit the SARS-3Clpro enzyme
activity (Lin et al., 2005, 2014). The flavonoid compound,
baicalin, from Scutellaria baicalensis was also discovered to
inhibit ACE (Chen and Nakamura, 2004; Deng et al., 2012;
Yang et al., 2020b). Fung et al. (2011) reported that a water
extract from Houttuynia cordata inhibited the activity of viral
3Clpro and blocked viral RNA-dependent RNA polymerase
activity (Lau et al., 2008). Subbaiyan et al. (2020) did a study
on 12 common herbal compounds and showed that the
compound epigallocatechin gallate (eGCG) had the highest
binding affinity to the viral S protein compared to curcumin,
apigenin, and chrysophanol. It is also reported that the
 6 DZOBO ET AL.
glycyrrhizin from the liquorice roots has been found to affect
the virus cellular signaling pathways (Goel and Goel, 2020).
A plausible strategy to prevent SARS-CoV-2 infection is
the use of natural compounds with the ability to inhibit viral
entry into host cells. SARS-CoV-2 is transmitted mainly
through droplets passed from one individual to another
through the nasal and oral routes (Wang et al., 2020b), al-
though the viral transmission dynamics and mechanisms are
still being deciphered and debated. Thus, inhibition of the
virus-receptor interaction is a possible strategy to prevent
infection (Dong et al., 2020; Patel and Verma, 2020; Sanders
et al., 2020). Cannabis sativa is a plant known to contain anti-
inflammatory compounds such as cannabinoid cannabidiol
(Machado Bergamaschi et al., 2011). In addition to other
compounds such as terpenes, these compounds have been
suggested to have potential anticancer properties. Like other
herbal plants, we suggest C. sativa warrants further mecha-
nistic research in relationship to putative effects in COVID-19.
The use of dietary supplements requires, however, further
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research and robust evidence base in relationship to COVID-
19. A notable ingredient of some of the herbal medicines,
supplements, and fruits is vitamin C. Studies have shown that
Vitamin C has antioxidant activity and may reduce oxidative
stress and inflammation, conditions observed in coronavirus
infection (Block et al., 2009; Mikirova et al., 2012). In ad-
dition, vitamin C is known to enhance vasopressor synthesis
and induce the immune system (Carr and Maggini, 2017; Lee
et al., 2003; Verlhac and Gabaudan, 1994). Use of the dietary
supplements needs to be researched as there are no known
clinical researches that demonstrate the efficacy of the dietary
supplements to specifically prevent or treat SARS-CoV-2.
Even though the efficacy of these plant compounds against
treatment of COVID-19 is not yet proven, there are no serious
side effects reported after using them, although this aspect also
requires further research in patients with different severity of
viral infection. There appears to be an interest toward traditional
and herbal medicine in societies in the case of COVID-19, but
this also requires rigorous research. Omics systems science
technologies offer prospects in this regard to transform herbal
medicine to precision herbal medicine. A related issue and a
current setback is present paucity of research funding for robust
evaluation, basic, translational, and clinical research toward
precision herbal medicine buttressed by omics systems science.
In sum, it is imperative that the scientific basis and
mechanism of action of herbal medicines are verified so they
can be supported by rigorous scientific evidence base. New
omics technologies such as glycomics offer new prospects in
this regard for they take into account molecular variations
such as carbohydrates and glycans beyond genomics (Kunej,
2019; Liu et al., 2019).
Conclusions
Once COVID-19 was declared a pandemic by the WHO,
governments worldwide have put extensive resources for
therapeutics and preventive medicine innovation against the
pandemic. Many already available drugs are being repurposed
or anticipated to find new use in a context of the pandemic
therapeutics. Several clinical trials, including those evaluating
the use of tocilizumab and dexamethasone, are underway with
results starting to emerge. Tocilizumab, dexamethasone, re-
mdesivir, favipiravir, and methylprednisolone call for addi-
tional research. Effective treatment of COVID-19 will
ultimately be biphasic in nature to address the disruption of the
immune system as well as other organ systems involved.
A big lesson from this pandemic is that repurposing of drugs
is an appealing option if we are to face future pandemics in the
21st century. Repurposing of drugs can easily avail drugs al-
ready in use, and redirect them to treat new threats to human
life. In addition, repurposing will likely reduce the time and
costs involved in finding a cure to new pandemics, as the
supply chain and formulations are already in place. Dex-
amethasone is more appealing compared to tocilizumab for the
treatment of severe cases of COVID-19 from the standpoint of
availability and costs. It is important to note that the use of both
tocilizumab and dexamethasone likely does not affect the
‘‘infection curve’’ as these drugs do not prevent the infection
itself. Thus, mitigating factors such as the wearing of masks
and keeping distances between individuals must still be the
main focus to prevent new infections.
Precision herbal medicines offer new promise for drug
discovery, provided that omics technologies can be utilized to
build a robust scientific evidence base on their clinical safety
and efficacy. Precision herbal medicine buttressed by omics
systems science would also help identify new molecular
targets for drug discovery against COVID-19.
Author Disclosure Statement
The authors declare they have no conflicting financial
interests.
Funding Information
The funding for this research was provided by the National
Research Foundation (NRF) of South Africa, South African
Medical Research Council, and the University of Cape Town.
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Kevin Dzobo, PhD
Division of Medical Biochemistry and
Institute of Infectious Disease and Molecular Medicine
Department of Integrative Biomedical Sciences
Faculty of Health Sciences
University of Cape Town
Anzio Road, Observatory
Cape Town 7925

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